In human retinal diseases, blindness is often caused by injury and death of photoreceptors and ganglion cells, such as in inherited retinal degenerations and in age-related macular generation, glaucoma, and optic nerve injury.
Basic fibroblast growth factor (bFGF) when injected into the eye can rescue photoreceptors in Royal College of Surgeon (RCS) rats which have an inherited retinal degeneration, and in rats that have been light damaged by exposure to constant light (see, for example, Steinberg, Curr. Opin. Neurobiology 4:515-524 (1994)).
Basic fibroblast growth factor (bFGF) is one of the best characterized members of a family of at least nine structurally related heparin binding growth factors (Baird Curr. Opin. Neurobiology 4:78-86 (1994)). bFGF exhibits neurotrophic activities (Wagner, J. A. Curr. Top. Microbiol. Immunol. 165:95-118 (1991); Baird Curr. Opin. Neurobiol. 4:78-86 (1994)), including retinal regeneration in vivo (Park et al. Int. Rev. Cytol. 146:49-74 (1993)).
In the brain, bFGF expression is elevated by various insults, including mechanical trauma, chemical injury, and ischemia (Wagner, J. A. Curr. Top. Microbiol. Immunol. 165:95-118 (1991); Baird Curr. Opin. Neurobiol. 4:78-86 (1994)). In addition, activation of .beta.-adrenergic receptors increased bFGF mRNA in rat hippocampus, cerebral cortex, and cerebellum (Follesa et al. Mol. Pharmacol. 43:132-138 (1993)). Recently, it has been shown in rat retina that bFGF mRNA was up-regulated by mechanical injury (Wen et al. J. Neurosci. 15:7377-7385 (1995)).
Increased bFGF immunoreactivity in the photoreceptors has been reported in both mouse and rat after optic nerve crush (Kostyk et al. J. Neurosci. 14:1441-1449 (1994)), whereas expression of bFGF mRNA was found to be elevated in mouse and rat after constant light exposure (Gao et al. Exp. Eye. Res. 62:181-189 (1996)). In addition, mechanical injury to the mouse or rat retina induced a marked increase in bFGF expression, and the greatest increase was found in the inner nuclear layer (Wen et al. J. Neurosci. 15:7377-7385 (1995)).
The neuroprotective activities of bFGF have been well studied (Wagner, J. A. Curr. Top. Microbiol. Immunol. 165:95-118 (1991); Baird Curr. Opin. Neurobiol. 4:78-86 (1994)) and evidence is accumulating that bFGF promotes photoreceptor survival. Optic nerve crush upregulates bFGF expression in photoreceptors (Kostyk et al. J. Neurosci. 14:1441-1449 (1994)), which is believed to result in photoreceptor protection against light damage in rats after optic nerve section (Bush et al. Exp. Eye Res. 52:139-153 (1994)). Gao and Hollyfield (Dev. Biol. 169:168-184 (1995); Exp. Eye Res. 62:181-189 (1996)) found that bFGF in photoreceptors was elevated in light-stressed mice and rats, and also in inherited mouse retinal degeneration models. They suggest that bFGF upregulation may function to enhance photoreceptor survival. In addition, upregulation of bFGF in retina by mechanical injury is believed to be responsible for the injury-induced photoreceptor rescue in RCS and light-damaged rats (Wen et al. J. Neurosci. 15:7377-7385 (1995)).
Also relevant to the instant invention are alpha- and beta-adrenergic receptors in the eye. Alpha-2-adrenergic receptors have been identified in the retina. Binding studies with bovine retinal membranes showed that the major .alpha.-adrenergic receptor in the retina was of the .alpha..sub.2 subtype (Bittiger et al. Nature 287:645-647 (1980); Osborne Vis. Res. 22:1401-1407 (1982)). Using [H.sup.3 ]para-aminoclonidine and autoradiography, Zarbin et al. (Brain Res. 374:75-92) mapped .alpha..sub.2 -adrenergic receptors in the rat retina. Recently, subtypes of alpha-2-adrenergic receptors have been characterized in the pig eye, and both the alpha-2A- and alpha-2C- subtypes are found in the retina (Wikberg-Matsson et al. Exp. Eye Res. 63:57-66 (1996)). Beta-adrenergic binding sites (beta.sub.1 and beta.sub.2 types) have been localized and characterized in the human eye (Elena et al. J. Ocular. Pharmacology (Summer, 6(2):143-9 (1990)); Elena, et al. Investigative Opth. 28:1436-1441 (1987)); Ferrari-Dileo Investigative Opth. 28:695-699 (1988)). The roles of the .alpha.- and .beta.-adrenergic receptors in the eye are not understood at this time.
A need exists for methods and compounds for use in the treatment of diseases of the retina. The instant invention addresses this need and others.